Background

Hydrops fetalis (fetal hydrops) is a serious fetal condition defined as abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema. In some patients, it may also be associated with polyhydramnios and placental edema. Hydrops is usually first recognized by ultrasonographic examination during the first or second trimester of gestation. Significant fluid collections are easily detected, but fluid accumulation may also be limited and thus escape routine ultrasonographic detection.

Hydrops fetalis has been a well-recognized fetal and neonatal condition throughout history. Until the latter half of the 20th century, it was believed to be due to Rhesus (Rh) blood group isoimmunization of the fetus. More recent recognition of factors other than isoimmune hemolytic disease that can cause or be associated with fetal hydrops led to the use of the term nonimmune hydrops to identify those cases in which the fetal disorder was caused by factors other than isoimmunization.

In the 1970s, the major cause of immune hydrops (ie, RhD antigen) was conquered with the use of immunoglobulin (Ig) prophylaxis in at-risk mothers. Before routine immunization of Rh-negative mothers, most cases of hydrops were due to erythroblastosis from Rh alloimmunization. With the introduction of widespread immunoprophylaxis for red blood cell alloimmunization and the use of in-utero transfusions for immune hydrops therapy, nonimmune causes have become responsible for at least 85% of all cases of fetal hydrops. Nevertheless, in developing countries, the incidence of immune fetal hydrops is still high.

Pathophysiology

Several hypotheses regarding the pathophysiologic events that lead to fetal hydrops have been suggested. The basic mechanism for the formation of fetal hydrops is an imbalance of interstitial fluid production and the lymphatic return. Fluid accumulation in the fetus can result from congestive heart failure, obstructed lymphatic flow, or decreased plasma osmotic pressure. The fetus is particularly susceptible to interstitial fluid accumulation because of its greater capillary permeability, compliant interstitial compartments, and vulnerability to venous pressure on lymphatic return.

Furthermore, the hepatic synthesis of albumin may be impaired owing to decreased hepatic perfusion and increased extramedullary hematopoiesis. Because albumin acts as the predominant oncotically active plasma protein, hypoalbuminemia increases transcapillary fluid movement at times of circulatory compromise.

Hydrops has been produced in the ovine fetus by anemia, tachyarrhythmia, occlusion of lymphatic drainage, and obstruction of cardiac venous return. Hypoproteinemia and hypoalbuminemia are common in human hydrops, and reduced intravascular oncotic pressure has been speculated to be a primary cause for the disorder. However, in the sheep model, a 41% reduction in total serum protein accompanied by a 44% decline in colloid osmotic pressure failed to produce fetal hydrops.
[2] Furthermore, a study in humans showed that, despite a significant negative correlation between the fetal serum albumin level and the degree of fetal hydrops, most fetuses with hydrops had albumin levels within the reference range.
[3] These results suggest that hypoalbuminemia is unlikely the sole cause for the primary onset of hydrops.

A closer look at the animal studies provides the clues necessary to understand the pathophysiology of hydrops. In one study, profound anemia was induced in fetal sheep; the hydrops that resulted was unrelated to hematocrit levels, blood gas levels, acid-base balance, plasma proteins, colloid oncotic pressure, or aortic pressure.
[4] The investigators found the difference was in the central venous pressure (CVP), which was much higher in persons with hydrops. The hematocrit level was reduced by 45% in a study of particular note; however, the CVP was maintained unchanged, and no fetus developed hydrops under these conditions.

Induced fetal tachyarrhythmia has led to fetal hydrops in several studies. Key to the development of fetal hydrops in these studies was an elevation in CVP; the anemia was only of indirect importance. The CVP was markedly elevated, with a range of 25-31 mm Hg in one study. In other reports, hydrops induced by sustained fetal tachycardia was unrelated to levels of blood gases, plasma protein, or albumin turnover; however, a 75-100% increase in CVP was observed in the fetuses that developed hydrops.

Excision of major lymphatic ducts produced fetal hydrops in sheep models. A related study demonstrated an exquisite, linear, inverse relationship between the lymphatic outflow pressure and the CVP; a rise in the CVP of 1 mm Hg reduced lymph flow 13%, and flow stopped at a CVP of 12 mm Hg.
[5] These results were confirmed by other observations of linear decline in lymph flow when the CVP exceeds 5 mm Hg and a cessation of flow at CVPs greater than 18 mm Hg.

Also of note is a computer simulation model in which cardiovascular and fluid electrolyte disturbances (eg, severe anemia, lymphatic obstruction, excess fluid and electrolyte loads, elevation in angiotensin levels) and compensating homeostatic mechanisms have been examined. This model demonstrated that "...fetal cardiac failure constituted the strongest stimulus for the formation of fetal edema...",
[6] thus further substantiating the pivotal role of CVP in the development of fetal hydrops.

Many other physiologic disturbances are associated with human fetal hydrops. Elevated levels of aldosterone, renin, norepinephrine, and angiotensin-I are likely to be secondary consequences. Although infusion of angiotensin-I led to fetal hydrops in nephrectomized sheep, the four-fold rise in the CVP was probably the primary cause of the hydrops. The meaning of increased levels of coenzyme Q10, placental vascular endothelial growth factor, and endothelin and decreased cytokine interleukin-3 levels is unclear at this time.

However, of particular interest is the three- to five-fold increase in atrial natriuretic peptide (ANP) that accompanies both human fetal hydrops (with cardiac anomaly or isoimmunization)
[7, 8, 9, 10] and ovine hydrops (induced by obstruction of venous return, sustained tachycardia, or induced anemia).
[11] A return of ANP levels to normal parallels the resolution of hydrops. These observations and the observations that vascular permeation of albumin is enhanced and cardiovascular and renal homeostatic adaptations are influenced by this peptide suggest an important role for ANP in fetal hydrops.

Evidence of low fetal plasma levels of cyclic guanosine monophosphate suggests that reduced nitric oxide production due to injury of fetal vascular endothelial cells may be involved in the development of fetal hydrops.
[11] This isolated observation requires confirmation and further study.

Despite numerous case reports, decades of clinical experience, and several research studies regarding the etiology and pathogenesis of hydrops, many questions still remain. Currently, which fetal neural and hormonal mechanisms induce and maintain the redistribution of blood flow, and which mechanisms allow metabolic disorders to cause hydrops, are almost completely unknown.
[1]

Previous

Next:

Etiology

Hydrops fetalis is a nonspecific finding that is easily detected using prenatal ultrasonography. Despite extensive pre- and postnatal investigations, including postmortem pathologic examination of the fetus, the etiology may remain unknown in about 15-25% of cases of nonimmune hydrops fetalis.

Most patients with hydrops diagnosed in early fetal life have chromosomal anomalies, whereas cases diagnosed after the second trimester are caused mainly by cardiovascular diseases. In a study 156 cases of hydrops in a neonatal intensive care unit (NICU), Lin et al found the major etiology and associated diagnosis consisted of 35.9% of nonimmune anemia, 9.6% of cardiac abnormalities, 7.1% of intrauterine infection, 6.4% of twin problems, 5.8% of meconium peritonitis, 5.1% of thoracic-lung disease, 4.5% of chromosomal abnormalities, and 1.9% of immune anemia.
[12] Alpha thalassemia was the most common nonimmune anemia (96%). An etiology and associated diagnosis could be determined in 81.4% of cases.
[12]

Diagnostic categories

Hydrops is an end-stage process for numerous fetal diseases. One study reviewed 225 relevant nonimmune hydrops fetalis articles that described 6,361 individuals.
[13, 14] The investigators established 14 different diagnostic categories, with all 6,361 patients subclassified into one of the following:

Rh disease was previouslyconsidered the usual cause of fetal hydrops. The use of RhoGAM in the at-risk mother, administered prior to maternal isoimmunization, should have made this an entirely preventable disorder. Sadly, this has not been the case. Although a dramatic reduction in RhD sensitization has been achieved with RhoGAM,
[17] the disorder has stubbornly persisted in a small group of women, many of whom have become isoimmunized from repeated exposure to foreign RBC antigens on contaminated needles used for administering illicit drugs. One study noted this cause for one in five women with Rh sensitization; the prevalence of hydrops in this group was a stunning 80%.
[18] More recently, the rise in illicit intravenous (IV) opioid use during pregnancy has been reported to lead to isoimmune hemolysis in the fetus, which results in fetal death or severe hydrops fetalis.
[19] Clinicians should be aware of this consequence; thus, careful history taking and screening is required.

The reduced prevalence of RhD disease has made fetal hemolytic anemias secondary to maternal isoimmunization with other Rh-group and other blood group antigens more apparent. Many of these result in profound fetal anemia and hydrops. Because many other such antigens are likely, maternal antibody screening should at least search for those already demonstrated to lead to fetal hydrops.

Molecular genetic technologies, specifically polymerase chain reaction (PCR) testing, have been particularly demonstrated to provide more precise and complete genotyping. Other heritable fetal hemolytic anemias have been associated with fetal hydrops. Most are uncommon, autosomal recessive genetic diseases (eg, pyruvate kinase deficiency, glucose phophate isomerase deficiency), and their association with fetal hydrops is limited to one or two reports. G-6-PD deficiency is a more common, X-linked recessive disorder; however, G-6-PD has been infrequently associated with fetal hydrops.

Making the diagnosis is important in these rare conditions, because they are compatible with a relatively normal life and fetal transfusions should be effective. Fetal RBC hemolysis from placental transfer of maternal immunoglobulin (Ig) G antibody against fetal RBC antigens (isoimmune disease) continues to account for approximately 15-20% of individuals with hydrops fetalis.

Early and precise diagnosis is of enormous importance, because highly effective fetal therapy is available and long-term outcome is unimpaired in infants with these causes for hydrops. Although fetal imaging confirms the presence of hydrops, it does so only after the fact. Thus, referral to a maternal-fetal medicine specialist is very beneficial. Studies preceding and predicting fetal deterioration include amniotic fluid bilirubin (delta optical density at 450 µ using Liley extrapolations), and measurement of fetal hematocrit and hemoglobin levels by direct sampling using cordocentesis. The degree of fetal anemia is indirectly measured by the middle cerebral artery velocity using Doppler ultrasonography.

Disorders of RBC production, resulting in functional fetal aplastic anemia, are particularly important causes of fetal hydrops. The role of infection with B19V is increasingly recognized. Use of a sensitive and precise diagnostic test (PCR) has demonstrated that perhaps 20% of fetal hydrops is associated with parvovirus infection. During seasons of particularly high prevalence, the proportion is much higher. Early diagnosis is crucial because fetal treatment by direct transfusion has been effective, the virus has no teratogenic effects, and growth and development of the survivors appear to be normal.

Heritable disorders of hemoglobin alpha-chain production are important causes of hydrops in Asian populations. These hemoglobinopathies have become increasingly relevant in the United States because of relatively recent immigration patterns, particularly in the West. A report from Hawaii over a 10-year period identified alpha-thalassemia as the single most important cause of fetal hydrops.
[20] Homozygous alpha-thalassemia, with deletion of all four alpha-globin genes, results in the total absence of alpha-hemoglobin chains in the fetus. This condition, ranging from 1 in 500 to 1 in 1500 in a Thai population, has been considered to be a fatal fetal condition (Bart hydrops).

A handful of survivors of hydrops fetalis due to alpha-thalassemia have been reported; however, all required fetal transfusions, all required repeated frequent transfusions after birth, and all surviving males had hypospadias.
[21] Thus, some healthcare professionals have questioned the practical and ethical basis of fetal and neonatal treatment. However, opportunities for treatment, such as stem cell transplantation, bone marrow transplantation, and gene replacement therapy, may hold promise for future infants with this condition. Fetal diagnosis of the condition has been confirmed (using PCR) from fetal DNA samples of chorionic villus, fetal fibroblast, and from fetal blood.

Once disorders of hemoglobin alpha-chain production are confirmed, fetal interventions have been based on hematocrit and hemoglobin levels obtained by direct cordocentesis. Ultrasonographic findings are nonspecific, and they occur late. Several simple maternal screening techniques have been suggested, but DNA-based studies using a testing system that allows unequivocal identification of haplotypes commonly detected in Asian Americans (-SEA in 62%, -alpha 3.7 in 27%, -FIL in 11%) appear to be most promising in this country. Despite the generally gloomy outlook and uncertain treatment of the infant with fetal hydrops, early diagnosis of the condition is essential as maternal morbidity is very high with fetal hydrops due to alpha-thalassemia. A multiplex PCR assay developed by Jomoui et al appears to show promise in providing an accurate prenatal diagnosis of Bart hydrops fetalis syndrome.
[15]

Other heritable disorders of RBC production are listed above, but none is very common. Some are fatal, but most are manageable after birth; some are associated with malformation syndromes. These heritable disorders all lead to hydrops in the same manner, as do the other conditions listed above.

Profound anemia leads to high-output cardiac failure and increased central venous pressure (CVP). Early and precise diagnosis is important for fetuses with correctable conditions (eg, need for and timing of fetal transfusions) and for fetuses with conditions that are not correctable (to permit parents to understand options and participate in decisions about pregnancy management). Gene therapy may also hold promise for some of these babies in the future.

Fetal hemorrhage is another important cause of fetal hydrops. Acute bleeding may be local or more generalized. Unless the origin is from a tumor mass, the bleeding may not be recognized early enough to intervene. Thus, fetal imaging is essential, and a careful examination, particularly of those sites where bleeding has been associated with hydrops, is essential for prompt and proper fetal treatment.

Isoimmune fetal thrombocytopenia is probably more common than has been reported and, because treatment may be effective in this condition, maternal screening for platelet antibodies should be routine in all cases in which the cause of fetal hydrops remains undetermined.

Sacrococcygeal teratoma is relatively common,
[22, 23] accounting for a measurable proportion of incidents of fetal hydrops. Controlled trials are needed to be certain that currently proposed interventions are more helpful than harmful, but these interventions hold considerable promise. Effective treatment is especially important for this condition because associated anomalies are rare, and fully normal development is possible. Once again, fetal imaging studies are the cornerstone for diagnosis and management of sacrococcygeal teratoma.
[24]

The fetus may bleed into the mother, and this hemorrhage may be severe enough to lead to fetal death or hydrops. Disruptions of the fetomaternal circulation may be placental or related to tumors (choriocarcinoma, chorangioma), trauma, or partial placental abruption.

Early diagnosis of fetomaternal hemorrhage requires a maternal blood smear to assess the proportion of circulating cells with fetal hemoglobin (resistant to acid elution). Unfortunately, automated modifications of this test are less specific and sensitive than the original Kleihauer-Betke test, and several newer tests have been proposed. Of these tests, the most promising appear to be either immunofluorescent flow cytometry or DNA analysis using PCR.It is difficult to determine which test to use and when to perform it because, in most reported cases, the diagnosis is usually too late to allow effective fetal intervention.

The earliest warning of the condition in most recent series has been reduced fetal body movements accompanied by sinusoidal fetal heart rate patterns and altered fetal biophysical profile. Confirmation of fetal anemia by direct cordocentesis is the final step to transfusion. Unfortunately, fetal transfusion has often been ineffective due to continued, repeated, massive fetal hemorrhages.

Placental vascular anastomoses are present in virtually all monochorionic monozygotic pregnancies. Twin-to-twin transfusion is balanced in most circumstances, with no excessive accumulation or loss for either twin. Sizable hemorrhages or unbalanced transfusion occurs in 5-30% of these pregnancies, leaving one twin anemic and the other polycythemic. This may lead to fetal death, impaired fetal growth, high-output cardiac failure from hypovolemic shock, congestive failure from volume overload, or hydrops fetalis, depending on the size of the bleed and whether it is acute or chronic. Extremely early twin-to-twin transfusion may result in fetal acardia; somewhat later, they may be detected as fetus papyraceous or as a stuck twin or vanishing twin.

Although some placental studies suggest fewer (rather than more) vascular anastomoses with resultant trapping of blood in the recipient fetus, other placental studies demonstrate excessive and abnormal placental vascular communications. Velamentous cord insertion is much more common in those fetuses with large shunts. Curiously, the recipient (polycythemic) twin usually develops hydrops, not the (anemic) donor. Even more interestingly, death of the hydropic twin (whether untreated and/or spontaneous, following fetal therapy, or after selective feticide) is not uncommonly followed by the development of hydrops in the remaining twin.

The reasons for all these events remain causes for speculation. Definitive diagnosis is also surprisingly difficult because hydrops may occur in either (or both) twin(s), disparities in fetal size may not be present, and fetal hemoglobin or hematocrit levels may be well outside the reference range (high or low) in the absence of any hydrops.

Ultrasonographic evidence of same-sex twins, a monochorionic placenta, with hydramnios in one sac and oligohydramnios in the other sac, is often used to make the diagnosis. These findings and disparities in fetal sizes (15%-25%) are useful, but unfortunately they are not definitive. Determination of fetal hemoglobins by cordocentesis is used; however, differences in fetal hemoglobin concentration exceeding 5 g/dL are common in the absence of hydrops and, conversely, differences less than this may be found in individuals with hydrops.

Significant differences in serum protein levels may also be observed in twins with hydrops fetalis, and atrial natriuretic factor (ANP) concentrations are usually high. Unfortunately, none of these findings are diagnostic. Clearly, earlier and more precise fetal diagnostic methods, which measure the degree of functional dysfunction, are needed.

Most promising in this regard are pulsed Doppler ultrasonographic measurements of umbilical vessel blood velocity. Such studies have the potential to provide an earlier window of opportunity for fetal diagnosis and treatment. The outcome is surprisingly poor in this condition. Most twins with hydrops die before birth (42%-86%), and a shocking proportion of survivors of the condition have cardiovascular and neurologic damage. Ultrasonographic studies demonstrate cerebral white matter damage, suggesting antenatal necrosis in approximately one third. Follow-up studies of neurodevelopment suggest serious impairment in approximately one quarter of surviving twins.

Many (if not most) surviving twins have significant cardiomyopathy (predominantly right-sided), usually associated with pulmonary outflow obstruction; pulmonary artery calcification and endocardial fibroelastosis are also common. Neutropenia, impaired fetal growth, reduced bone density, and mineralization have been observed in the surviving donors. Optic nerve hypoplasia has been reported, and peripheral vascular ischemic necrosis with gangrene of the distal extremities has been observed in several individuals with the condition. Coagulopathy and embolic phenomena were speculated in many early studies; however, scant evidence for them is present in more recent reports. Very premature delivery is common and undoubtedly contributes to the morbidity and mortality.

Treatment successes have been reported with transfusion of the anemic fetus, plasmapheresis of the polycythemic twin, laser ablation of placental vascular anastomoses, and amnioreduction; however, failures and serious complications have also been reported with each of these. See Twin-to-Twin Transfusion Syndrome.

Hydrops fetalis is the final common hemodynamic pathway for various fetal cardiovascular pathologies, including high-output states associated with fetal anemia or arteriovenous fistulas and abnormalities of both cardiac structure and rhythm. Cardiovascular problems that cause or are associated with hydrops are summarized below. Although extensive, the list is inevitably incomplete because new associations are reported each year.

Cardiac causes

Common cardiac causes include structural anomalies, dysrhythmias, tumors, as well as cardiomyopathy and myocarditis.
[25]

Structural anomalies

Abnormalities of left ventricular outflow include the following:

Aortic valvular stenosis

Aortic valvular atresia

Coarctation of the aorta

Aortico-left ventricular tunnel

Atrioventricular canal

Left ventricular aneurysm

Truncus arteriosus

Hypoplastic left heart

Spongiosum heart

Endocardial fibroelastosis

Abnormalities of right ventricular outflow include the following:

Pulmonary valvular atresia or insufficiency

Ebstein anomaly

Other vascular malformations include the following:

Arteriovenous malformations (AVMs)

Diffuse hemangiomatosis

Placental hemangioma

Umbilical cord hemangioma

Hepatic hemangioendothelioma

Abdominal hemangioma

Pulmonary arteriovenous fistula

Cervical hemangioendothelioma

Paratracheal hemangioma

Cutaneous cavernous hemangioma

AVMs of the brain

Nonstructural anomalies

Obstruction of venous return includes the following:

Superior or inferior vena cava occlusion

Absent ductus venosus

Umbilical cord torsion or varix

Intrathoracic or abdominal tumors or masses

Disorders of lymphatic drainage

Other cardiac nonstructural anomalies include the following:

Supraventricular tachycardia

Congenital heart block

Prenatal closure of the foramen ovale or ductus arteriosus

Myocarditis

Idiopathic arterial calcification or hypercalcemia

Intrapericardial teratoma

Cardiovascular diseases are one of the main causes for nonimmune hydrops fetalis. Congenital structural anomalies of the heart may be present in as many as one in four infants with hydrops; both right-heart and left-heart anomalies, systolic-overload and diastolic-overload conditions, high-output conditions, and congestive situations are represented. Although many cardiac malformations have been reported, the most common were atrioventricular (AV) septal defects.

Structural cardiac defects are commonly accompanied by other anomalies and are often associated with cytogenic abnormalities. Examples include the association between coarctation of the aorta and Turner syndrome, the relationship between the AV canal and/or endocardial cushion defects and Down syndrome, and the common association of Turner syndrome with cystic hygroma, left-sided lymphatic flow defects, and left-heart outflow defects.

Fibroelastosis may be an isolated abnormality; however, fibroelastosis more commonly represents an endocardial response to chronic fetal myocardial stress. Prenatal detection of a cardiac defect should always trigger a careful search for other malformations, and karyotyping should be performed in all such fetuses. AVMs are the often cited causes of hydrops; they are listed individually above.

Impaired right-heart filling is also an important cause of hydrops. Although uncommon, umbilical or vena caval thromboses have been noted. Theoretically, they may be correctable if diagnosed early enough. Conversely, tumor compression is a frequently reported cause of hydrops. Several of these masses involve lymphatic malformation and/or obstruction; cystic hygroma is a particularly notable example.

Prenatal closure of the foramen ovale or ductus arteriosus prematurely converts the (parallel) fetal circulation to a (serial) postnatal circulation; the associated problems are obvious. Most recorded instances of premature ductal closure are iatrogenic, related to maternal administration of indomethacin or sodium diclofenac.

Several instances of idiopathic arterial calcification with hydrops have been reported. In one such incident, fetal serum calcium levels were elevated, and a possible association with Williams syndrome was suggested. In three other cases, lysosomal storage diseases were present (Gaucher, sialidosis, galactosialidosis). No associations were noted in four cases. Hydropic recipients of twin-to-twin transfusion who survive also usually have pulmonary artery calcification.

Fetal supraventricular tachycardias are important causes of hydrops because they can be diagnosed accurately by cardiac imaging in early pregnancy, they may be treated effectively before hydrops develops and, because associated malformations or syndromes are rare, they have anticipated good outcomes. Whether an AV block is present (atrial flutter) or not (tachyarrhythmia), survival rates of 85%-95% are typical, and neurodevelopmental outcome is usually normal. Males are affected more than in females (2:1). Clinical experience and animal model studies indicate that hydrops can occur with sustained cardiac rates of less than 220-230 beats per minute (bpm) and that the risk is related directly to the degree of prematurity.

Congenital heart block is also often associated with hydrops. The diagnosis is made using cardiac imaging or with an electrocardiogram (ECG) in the newborn; rates are always less than 90 bpm and usually below 65 bpm. Approximately two thirds to three fourths occur in pregnancies complicated by maternal collagen disease. Maternal immunoglobulin (Ig) G antinuclear antibodies cross the placenta and attack fetal collagen in the conduction bundle. Why some fetuses develop congenital heart block and others do not is unclear; however, an association with human leukocyte antigen (HLA) types (HLA-DR3, among others) has been suggested.

Treatment with various drugs has generally been unsuccessful, as has fetal surgery for pacing. Evidence exists to suggest corticosteroid therapy may be of benefit.

Virtually all of the remaining babies, whose mothers have no collagen disorder, have serious, complicated, cardiac structural defects. The most common lesions are AV canal and/or endocardial cushion defects, transposition of the great vessels, and other isomerisms. The outcomes for these babies are grim. Mortality is 25%-35% if the cardiac structure is normal; however, many survivors require neonatal surgery for pacing, and sparse information is available on long-term outlook. Because the cardiac structural abnormalities are so serious and complex, mortality and morbidity are much higher if cardiac anomalies are present.

Infectious causes

The immature fetus is particularly susceptible to overwhelming viral and bacterial infection. Those pathogens that do not kill quickly may cause smoldering generalized infections with myocarditis, suppressed erythropoiesis and myelopoiesis, hemolysis, and hepatitis. Such infections may lead to hydrops fetalis. Several causative pathogens reported to date are listed below. Among the infectious etiologies, the most common causes are cytomegalovirus (CMV), toxoplasmosis, syphilis, and B19V infection.

The association of congenital syphilis with hydrops is classic. Fetal and placental edema accompanied by serous effusions first was described generations ago. However, the surprising frequency with which maternal serologic tests for syphilis may appear negative in this condition is less well known.

The prozone phenomenon, observed during primary and secondary maternal syphilis, occurs when a higher-than-optimal amount of anti-syphilis antibody in the tested maternal sera prevents the flocculation reaction typifying a positive result in reagin tests. In these circumstances, dilution of the tested serum is necessary to make the correct diagnosis. Thus, serum dilution (to as much as 1:1024 or greater) should be routine in high-risk situations and should certainly be used in any individual in whom fetal hydrops of unknown etiology is present.

Early, accurate diagnosis of this infection is critical because fetal treatment is available and effective. Several viral infections have been associated with fetal hydrops. The number of viruses implicated and the frequency of these cases have paralleled the increased recognition of this association and the improved simplicity and sensitivity of diagnostic methods. Hydrops in these conditions appears to be the cumulative result of viral effects on marrow, myocardium, and vascular endothelium. Currently, reports of effective fetal treatment are rare.

Human parvovirus B19 is a single-stranded DNA virus that usually infects rapidly dividing cell lines, such as erythroid progenitor cells. An estimated 1%-5% of pregnant women are infected with parvovirus B19.
[16] This virus has been shown to cause a congenital infection syndrome, manifested by rash, anemia, hepatomegaly, and cardiomegaly, and infection can lead to miscarriage or nonimmune hydrops fetalis.
[16] Because most pregnant women who become infected with B19V are asymptomatic, determining the risk of fetal infection, fetal wastage, and nonimmune hydrops fetalis is difficult.

In infected pregnant women, B19V is believed to affect the fetus approximately 30% of the time; however, only 2%-10% of infected fetuses experience poor outcomes. Some evidence has demonstrated that acute B19V infection is a common cause of fetal hydrops.
[29] The virus was first identified in 1974 and was first linked with fetal hydrops 10 years later. Evidence published since then suggests this virus may be the single most important currently recognized cause of fetal hydrops. Parvovirus may be the cause of as many as one third of all incidents of hydrops fetalis.

The outcome following B19V infection is surprisingly good; spontaneous resolution occurs in approximately one third of such incidents, and approximately 85% of those who receive fetal transfusions survive. The virus is not teratogenic and, despite reports of viral persistence in myocardial and brain tissues, neurodevelopmental outcome in survivors appears to be normal. Early, accurate diagnosis, using maternal serologic and/or molecular biologic PCR techniques, is essential. Positive results are usually confirmed by direct fetal PCR, hemoglobin, hematocrit, and platelet studies to determine a proper treatment plan.

An interesting association between hydrops and fetal meconium peritonitis is also recognized. At least 16 such cases are found in the literature. No baby reported before 1991 had evidence of infection; however, CMV (1), hepatitis B (1), and B19V (5) were found in 7 of 8 cases reported since 1991. The only instance of meconium peritonitis and hydrops without confirmed infection in these later reports was likely iatrogenic, because it followed paracentesis with subsequent placement of a peritoneoamniotic shunt. These observations suggest that the coexistence of hydrops and meconium peritonitis should be assumed to be related to fetal infection until proven otherwise.

LCMV is a member of the Arenavirus family that mainly infects small rodents. Humans may become infected by inhalation of the virus particles when in contact with infected rodent urine. In immunocompetent humans, LCMV infection is mostly asymptomatic but it may cause mild febrile illness with aseptic meningitis, which is rarely fatal.

The incidence of LCMV infection during pregnancy is unknown but several cases of congenital infection have been reported. The main features of congenital LCMV infection include chorioretinitis, hydrocephaly or microcephaly, periventricular calcifications, and seizures. Fetal infection may result in fetal or neonatal death, and neurologic sequelae affect 84% of the surviving infants.

One report suggested that LCMV should be added to the list of causative agents of nonimmune hydrops fetalis.
[28] These viruses should be screened for in cases of unexplained fetal hydrops, especially when there is a possibility of maternal contacts with rodents and postmortem findings are suggestive of fetal infection.

Hydrops fetalis has been associated with more than 75 inborn errors of metabolism, chromosomal aberrations, and genetic syndromes. Approximately 50 of the more common errors are listed below. An additional 20 or more reports of imprecisely defined chromosomal or genetic syndromes identify hydrops as an incidental finding.

The heterogeneity of this collection of associations is bewildering at first glance. However, the common thread that runs through them is useful for understanding: Most of the infants with hydrops associated with the conditions listed above have severe complex cardiac defects, disorders of lymphatic drainage, AVMs, impaired production of properly functioning RBCs, and/or thoracoabdominal masses that impair venous return to the heart. Thus, the same disturbed pathophysiology identified as causing hydrops in the animal studies is reflected in these conditions.

Inheritance for most of these conditions (when known) is autosomal, most often recessive. Because a few of these conditions are X-linked recessive, slightly more males are affected among this particular set of causes. Gene therapy may hold therapeutic promise for the future; however, outcomes are generally grim for babies with hydrops related to these etiologies. Accurate diagnosis is particularly important in affected infants despite their poor prognosis, because parental counseling is critical in the management of current and future pregnancies for these families.

Fetal hydrops has been associated with approximately 10 of the approximately 50 lysosomal storage disorders. Little doubt appears to exist that hydrops will be linked with most such inborn errors of metabolism in the near future.

Cystic hygroma are commonly associated with complex profound aberrations of lymphatic drainage. These lesions are usually found in the neck but may also be present in the abdomen or thoracic cavity. The incidence of cystic hygroma has been reported to be as high as 1 in 6,000 at birth and as high as 1 in 750 among spontaneously aborted fetuses.

Although some authors have reported cases of live birth after spontaneous resolution of the cystic lesion, the prognosis remains poor if the hygroma is associated with hydrops fetalis irrespective of karyotype. Two thirds to three fourths of fetuses with this tumor have chromosomal abnormalities (most commonly 45,XO), and those fetuses with normal chromosomes often have major malformations. The associations with Turner, Noonan, and lethal multiple pterygium syndromes are particularly notable.

Mortality is extremely high (85%-96%), but early precise diagnosis is important for the purposes of genetic counseling and pregnancy management. One report detailed a case of a fetus in which fetal cystic hygroma and hydrops fetalis spontaneously resolved, with subsequent delivery at 37 weeks' gestation of a living female infant with Noonan syndrome.
[30]

Thoracic and abdominal tumors are common causes of fetal hydrops. This association makes physiologic sense because the location and size of these masses are likely to obstruct the return of venous or lymphatic fluids to the heart. Some tumors are commonly associated with major malformations and/or chromosomal abnormalities and, consequently, have a poor long-term prognosis. For example, upper airway obstructions are associated with other major malformations in more than half of the cases reported, and the association of fetal rhabdomyomas with tuberous sclerosis and complex cardiac malformations is well recognized.

Venous return is directly impaired by such conditions as pericardial teratomas and cardiac rhabdomyosarcomas. Upper airway (laryngeal, tracheal) atresia or obstruction leads to massive pulmonary overdistention and, thus, to impaired cardiac filling. Cystic hygromas are mentioned again because they comprise an important and common example of mass compression with obstruction of venous-lymphatic return. Meconium peritonitis is noted in tumor or mass causes and in the discussion of infectious causes. This redundancy is due to the fact that some observers have postulated an association with hydrops on the basis of mass effects on venous return; as noted earlier, the association is almost certainly one with fetal infection and consequent RBC aplasia.

Some of these conditions may lead to fetal hydrops not because of mass compression effects but because their intense vascularization may lead to arteriovenous shunting and/or to massive fetal hemorrhage. Such consequences are especially common with sacrococcygeal teratomas and with placental chorioangiomas. In both instances, fetal high-output cardiac failure may ultimately lead to fetal hydrops and/or death. Sacrococcygeal teratoma is associated with hydrops in one fifth to one third of cases in several case series; fetal coagulopathy, most commonly thrombocytopenia, is found in approximately the same proportion of cases. Tumor size as assessed using ultrasonography has not been demonstrated to be an independent prognostic factor; however, solid, highly vascular tumors lead to hydrops more often than those with a more cystic, less vascular structure.

Because chromosomal abnormalities and life-threatening anomalies are rare with sacrococcygeal sequestration, early diagnosis and aggressive fetal treatment are particularly important with this condition. Although bloody amniotic fluid secondary to the rupture of the highly vascular teratoma is not uncommon, the diagnosis in most cases has been made only after hydrops has developed.

Early routine fetal imaging may be the only way in which early diagnosis can be made in this condition; however, the low incidence of sacrococcygeal teratoma may preclude cost-effective screening for this condition. Elevated concentrations of alpha-fetoprotein (AFP) and/or acetylcholinesterase in the amniotic fluid have been found to accompany fetal sacrococcygeal teratoma, but the invasive sampling and low specificity appears to preclude these tests as routine screening procedures. Although placental chorioangiomas are common (present in approximately 1% of pregnancies), large vascular tumors with cardiovascular and hematologic consequences are very uncommon. When present, the pathophysiology of placental chorioangiomas is remarkably similar to that found with fetal sacrococcygeal teratomas. The diagnosis and techniques for early intervention are also similar.

Bronchopulmonary sequestration is a condition in which abnormal vascular supply and misplacement of a portion of the lung may lead to torsion of the affected lobes, profound obstruction of lymphatic and venous return, and tension hydrothorax. This sequence of events leads to fetal hydrops in perhaps one third of such cases. Although drainage of the hydrothorax, definitive diagnosis using color Doppler imaging, and fetal angiography have been described, and although fetal surgical excision of the affected portion of the lung may improve survival in this condition, nearly two thirds of these cases fail to be diagnosed before fetal death or birth occurs.

Congenital pulmonary airway malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CAM), is a rare abnormality of lung development in which there is a hamartomatous overgrowth of the terminal bronchioles with subsequent suppression and lack of differentiation of the alveoli. CPAM of the lung may also lead to hydrops by mass compression of venous return.

Because CPAM is seldom associated with other malformations or with chromosomal abnormalities, and because fetal surgical maneuvers have demonstrated considerable promise with some forms of the disorder, early and precise diagnosis using fetal imaging techniques is critical. CPAM is a rare fetal lung disease with an excellent prognosis in the absence of fetal hydrops. CPAM associated with fetal hydrops carries a grave prognosis, but survival rates of 70% can be achieved by thoracoamniotic drainage in those with macrocystic lesions. Lee at al reported successful treatment of hydrops associated with CPAM using fetal percutaneous sclerotherapy by ethanolamine injection into the tumor and concluded that fetal percutaneous sclerotherapy can be used as a minimally invasive palliative strategy to treat CPAM-induced hydrops fetalis.
[32]

Pulmonary capillary-alveolar development is abnormal in this condition, and three degrees of severity, described initially by Stocker, have been used to predict prognosis, as follows
[33] :

Type I: Fetuses with large (>2 mm), isolated cysts seldom develop hydrops, and spontaneous remissions have been reported. Drainage or excision of individual cysts has also been reported with generally favorable outcomes.

Type II: Poorer prognosis is associated in fetuses with smaller (<2 mm) diffuse macrocysts, and isolated fetal pulmonary excisions have been proposed in those who develop hydrops.

Type III: In fetuses with microcystic disease, the affected lung appears solid, hydrops is common, and the outcome is generally unfavorable.

Compression of fetal lung, common with many of the tumor and mass etiologies, not only impairs cardiac return but also has an additional particularly serious consequence. External compression of developing fetal lung is known to impair both anatomic and biochemical maturation. Pulmonary hypoplasia, with a profound reduction in the number of functional alveolar units, is a common finding when fetal hydrops accompanies these conditions. Delayed or impaired maturation of pulmonary surfactant production is another consequence of impaired expansion of the fetal lung, thus worsening the already serious compromise of extreme prematurity in these babies.

Previous

Next:

Epidemiology

United States data

The precise incidence of hydrops fetalis is difficult to elucidate, because many cases are not detected prior to intrauterine fetal death and some cases may resolve spontaneously in utero. The best estimate for how common this condition is in the United States is approximately 1 in 600 to 1 in 4,000 pregnancies. The incidence of immune hydrops has significantly decreased with the wide use of passive immunization using Rh immunoglobulin for Rh-negative mothers at 28 weeks' gestation (following suspected fetomaternal hemorrhage) and postpartum (following the delivery of an Rh-positive infant). The efficacy of this program has been demonstrated by a decline in the incidence of Rh hemolytic disease of the fetus or newborn, from 65 in 10,000 births in the United States in 1960 to 10.6 in 10,000 births in 1990.

More recently, data from the California Office of Statewide Health Planning and Development (2005-2012) reported in 2017 showed an incidence of 2.5 per 10,000 live-born infants with nonimmune hydrops fetalis.
[34]

International data

Hydrops fetalis is much more common in Southeast Asia. The best figures come from Thailand, where the expected frequency of hydrops, from homozygous alpha-thalassemia or Bart hydrops alone, is 1 in 500 to 1 in 1,500 pregnancies.
[35] A 2017 report of the genetic origin of α0-thalassemia (SEA deletion [-SEA]) in Southeast Asian populations found that 94.0% of Thai, 100% of Laotian, and 100% of Cambodian α0-thalassemia alleles were linked to haplotype H4 (AAGC), with a G allele (rs3760053) having a strong linkage disequilibrium with the α0-thalassemia allele.
[15]

Accurate figures from the Mediterranean region are not available; however, the commonness of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and of defects in alpha-chain hemoglobin production in several populations from this region lead to the suspicion that the incidence of hydrops in that region is much higher than it is in the United States.

Race-related demographics

Ethnic influences are related almost entirely to cause. Selected examples include the importance of genetic variations in the alpha-chain structure of hemoglobin in Asian and Mediterranean populations in addition to the more serious nature of the hemolytic disease in black fetuses affected by maternal ABO-factor isoimmunization.

Sex-related demographics

Sex influences in incidence or outcome of hydrops fetalis are largely related to the cause of the condition. A significant proportion of fetal hydrops is caused by or associated with chromosomal abnormalities or syndromes. Many of these are X-linked disorders.

Because most individuals with hydrops fetalis are delivered quite prematurely, and because fetal pulmonary maturation takes place earlier in female than in male fetuses, male preterm infants are at greater risk for the pulmonary complications of a very preterm delivery. They are also at greater risk for infections (nosocomial or otherwise), which are quite common in very preterm infants. A striking example of the greater male risk is the nearly 13-fold increase in the odds ratio for development of hydrops in the male fetus with RhD hemolytic disease. Although a single precise risk figure is not available for the heterogeneous collection of cases that comprise hydrops fetalis, male fetuses appear to have a greater risk for occurrence, morbidity, and mortality.

Previous

Next:

Prognosis

Fetal hydrops carries a poor prognosis, especially in preterm infants, remains a complex condition with high mortality and morbidity.
[38] The prognosis partly depends on the underlying disease. The growing number of recognized etiologies requires a comprehensive and systematic search for causes, in particular for treatable or recurrent conditions.
[39] Several diseases can be treated in utero with potential good results; with aggressive postnatal care, the survival rate is increased in selected cases.

The outcome of hydrops fetalis also depends on gestational age at birth and serum albumin level. One study suggested that hydrops resulting from lymphatic malformations has a favorable outcome.
[40] Preterm birth at less than 34 weeks' gestation and a serum albumin concentration level of less than 2 g/dL are poor prognostic factors for survival. A strong association has been reported between gestational age, the presence of two or more serous cavity effusions, and poor outcome in infants with hydrops fetalis.
[41] More recently, investigators revealed that signficant factors for postnatal death in fetal hydrops infants with pleural effusion are gestational birth week and standard deviation score of birth weight.
[38]

Outcomes in fetuses with antenatally diagnosed idiopathic nonimmune hydrops fetalis are similarly dependent on the underlying etiology, with the presence of ascites a prognostic factor for perinatal mortality.
[42] Unfortunately, fetal intervention in patients with nonimmune hydrops fetalis does not appear to offer a survival advantage.

Morbidity/mortality

The diagnosis and management of fetal hydrops have improved with advances in prenatal diagnostic and therapeutic interventions in conjunction with the advances in neonatal intensive care. However, fetal hydrops is still associated with a high mortality rate.

Estimates of mortality vary widely, from nearly zero to virtually 100%. Most case series report a 60%-90% mortality, although some improvements are notable in more recent reports. Many reasons for these variations are recognized, not least of which include the sophistication of diagnostic methods used and the complexity and costs of treatment.

However, the most important single factor is the cause of the hydrops. A significant proportion of these cases are caused or accompanied by multiple and complex congenital malformations of genetic and/or chromosomal origin, which by themselves are fatal at an early age. Many other causes are accompanied by masses or fluid accumulations, which compress the developing fetal lung and preclude its normal development. Thus, the presence or absence and potential prevention of pulmonary hypoplasia are of crucial importance.

One study showed that mortality rate was highest among neonates with congenital anomalies (57.7%) and lowest among neonates with congenital chylothorax (5.9%).
[43] Infants who died were more likely to be more premature, were sicker after birth, with lower 5-minute Apgar scores, and needed higher levels of support during the first day after birth.

Another highly important factor is the very premature delivery of most babies with hydrops consequent to conditions that distend the uterus and provoke early labor, or to therapeutic interventions (eg, fetal thoracentesis, paracentesis, complex fetal surgical procedures).

A 2017 report of data from the California Office of Statewide Health Planning and Development (2005-2012) regarding 1037 live-born infants with nonimmune hydrops fetalis revealed a 35.1% neonatal mortality and a 43.2% overall mortality at age 1 year.
[34] Poor prognostic factors were prematurity, polyhydramnios, and large for gestational age.

In a separate 2017 report that analyzed data from an international registry of 69 survivors with hemoglobin Bart hydrops fetalis, investigators found that more than half survived beyond age 5 years (n = 39; 56.5%), of whom half (n = 18; 26.1%) were older than 10 years.
[44] Although intrauterine therapy appeared to be beneficial during the perinatal and neonatal periods, the investigators suggested that further benefits might not extend to long-term growth and neurodevelopment outcomes. Indeed, over time, about 40% of these patients had severe weight retardation and 50% had height retardation, and 20% had a neurodevelopment delay of 6 months or longer.
[44]

Faber JJ, Anderson DF. Angiotensin mediated interaction of fetal kidney and placenta in the control of fetal arterial pressure and its role in hydrops fetalis. Placenta. 1997 May. 18(4):313-26. [Medline].